2-alkoxyestrogen derivatives are steroid compounds which have or might have therapeutic value. In this respect, 2-methoxyestradiol, a physiological urinary metabolite of endogenous estradiol, has been reported to be an anticancer agent of high clinical relevance for many tumour types.
In U.S. Pat. No. 5,504,074, continuation U.S. Pat. No. 5,661,143 and divisional U.S. Pat. No. 5,892,069 there are claimed methods of treating mammalian diseases characterized by undesirable angiogenesis and abnormal mitosis, respectively, by administering 2-methoxyestradiol.
In U.S. Pat. No. 5,643,900 there is claimed a method of suppressing the growth of solid tumours sustained by angiogenesis in mammals comprising administering 2-methoxyestradiol.
In U.S. Pat. No. 5,958,892 there is claimed a method of treating a patient having a tumour comprising the step of administering a p53 gene in combination with 2-methoxyestradiol.
In WO02/42319 there are claimed compositions and methods for treating mammalian diseases characterized by undesirable angiogenesis by administering 2-methoxyestradiol.
2-Methoxyestradiol is reported to have multiple mechanisms of action, to be orally available, non-toxic, rapidly excreted, non-estrogenic. For a short but comprehensive review, see for example Pharmacotherapy, 23, 165, (2003).
In J. Med. Chem. 40, 2323, (1997), 2-ethoxy and 2-(2,2,2-trifluoroethoxy) estradiol analogues with enhanced biological effects are disclosed.
In J. Med. Chem. 47, 5126, (2004), certain 17 alkyl derivatives of 2-methoxyestradiol with enhanced metabolic stability are reported.
Processes for the preparation of 2-methoxyestradiol are known, and all refer to two general methodologies for the preparation of 2-alkoxyestrogens from estradiol or estrone as starting materials.
One methodology entails generally the halogenation at C-2 of a suitably protected estradiol or estrone followed by a nuclophilic displacement of the halogen atom by the alkoxy moiety. A variety of conditions have been employed. See, for example, U.S. Pat. No. 6,051,726; U.S. Pat. No. 6,054,598; Hunan Daxue Xuebao, Ziran Kexueban 24, 40, (1997) (C.A. 128:180572); Sichuan Daxue Xuebao, Ziran Kexueban 27, 106, (1990) (C.A. 114:6922); Youji Huaxue 9, 266, 1989 (C.A. 111:195225); Steroids 471, 63-6 (1986); Sichuan Daxue Xuebao, Ziran Kexueban 114, (1986) (C.A. 107:176307); J. Chem. Res., Synop. 348, (1985); J. Chem. Soc., Chem. Commun. 533, (1983); Synthesis 168, (1977). Besides the need of protection/deprotection steps, the aromatic halogenation reaction provides also varying amounts of 4- and 2,4-halogenated intermediates in addition to the desired 2-halogen regioisomer, which consequently should be carefully separated from the unwanted regioisomers before proceeding in the synthesis.
The second methodology entails generally the aromatic acylation at C-2 of a suitably protected estradiol or estrone obtained by either a Friedel Craft-type direct acylation or the above mentioned haloderivative. In both cases, mixture of regioisomers may be obtained. A Baeyer-Villiger oxidation follows to provide a 2-acyloxy derivative, which is hydrolized and the resulting phenolic moiety is etherified with a suitable alkylating agent. A variety of conditions have been employed. See, for example, U.S. Pat. No. 6,051,726; U.S. Pat. No. 6,054,598; Synth. Commun. 28, 4431, 1998; Bioorg Med. Chem. Lett. 4, 1725, (1994); J. Am. Chem. Soc. 80, 1213, (1958). The desired product is obtained after a deprotection step.
Neither 2-aryloxyestrogen compounds nor their methods of preparation have been previously disclosed.
Since estradiol and 19-nortestosterone (nandrolone) are commercially available bulk materials which are similarly quoted on the global market, we addressed the practical issue of using 19-nortestosterone as an alternative starting material in lieu of estradiol/estrone, and have now found a process route to 2-alkoxy and 2-aryloxy derivatives of estradiol and estrone starting from 19-norsteroid derivatives. The instant route, entailing advantageously a straightforward aliphatic chemistry with no use of any protecting group, implies the aromatization of the ring A of the 2-alkoxy (aryloxy)-19-norsteroid derivative as the ultimate step. In addition, certain of the process intermediates may have therapeutic applications or are physiological precursors to therapeutic agents.